Furaneol glycoside compound, pharmaceutical composition thereof, preparation method therefor, and application thereof

ABSTRACT

Disclosed are a furaneol glycoside compound, a pharmaceutical composition thereof, a preparation method therefor, and an application thereof. Specifically disclosed are a compound as represented by formula A-1, a pharmaceutically acceptable salt thereof or a crystal form thereof. Also disclosed is a pharmaceutical composition, which comprises the compound as represented by formula A-1, the pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant. Also disclosed is an application of the compound as represented by formula A-1, the pharmaceutically acceptable salt thereof, the crystal form thereof, or the pharmaceutical composition in the preparation of drugs. The drugs are drugs for treating inflammatory bowel diseases. The furaneol glycoside compound has a good effect of treating inflammatory bowel diseases, particularly ulcerative colitis.

This application claims priority of the Chinese Patent Application2019113270637, filed on Dec. 20, 2019, the contents of which areincorporated herein by reference in their entireties.

TECHNICAL FIELD

The present invention relates to the field of pharmaceutical technology,and in particular, to a furaneol glycoside compound, a pharmaceuticalcomposition thereof, a preparation method therefor, and use thereof.

BACKGROUND ART

Inflammatory bowel disease (IBD) is a chronic and recurrent intestinalinflammatory disease. Based on different pathological characteristicsclinically, inflammatory bowel disease can be divided into two majorcategories, ulcerative colitis (UC) and Crohn's disease (CD). Ulcerativecolitis is an inflammatory disease of the rectal and colonic mucosa,mainly affecting the mucosa and submucosa of the colon. Crohn's diseasemainly affects the terminal ileum and adjacent colon and can involve thegastrointestinal tract in a phased and asymmetrical distribution. Theincidence of inflammatory bowel diseases varies geographically. NorthernEurope, the United Kingdom, and North America have the highest incidenceof inflammatory bowel diseases, with a prevalence of 200-300/100,000.Asia and most developing countries have a lower prevalence ofinflammatory bowel diseases, with a prevalence of 10-20/100,000. Withthe development of the economy, the incidence of inflammatory boweldiseases is on the rise in many newly industrialized countries inAfrica, Asia, and South America. At the beginning of the 21st century,inflammatory bowel disease has become a global disease.

At present, there are many treatment options for inflammatory boweldiseases, but pharmacotherapy remains the mainstay for the treatment.Traditional aminosalicylic acids have been used to treat inflammatorybowel diseases for 50 years. However, aminosalicylic acids are nottolerated by more than 30% of patients, and aminosalicylic acids cancause side effects such as hepatic impairment, renal impairment, andgastrointestinal reaction. Thiopurines are currently the most widelyused immunosuppressive agents for inflammatory bowel diseases. However,about 5% of patients using thiopurines have anaphylaxis, hepaticimpairment, and myelosuppression, so it should be monitored throughoutthe treatment and reviewed regularly. Other biological agents, such asthe human-mouse chimeric TNF-α monoclonal antibody infliximab, canimprove the clinical symptoms and endoscopic lesions of Crohn's disease.However, infliximab is not widely used due to its high price andpotential risks such as the increased likelihood of contractingtuberculosis. Therefore, it is urgent to develop new drugs with higherefficacy and fewer side effects for the treatment of inflammatory boweldiseases.

CONTENTS OF THE INVENTION

The technical problem to be solved by the present invention is toovercome the defect of the single structure of existing compounds fortreating inflammatory bowel diseases, and provide a furaneol glycosidecompound, a pharmaceutical composition thereof, a preparation methodtherefor, and use thereof. The furaneol glycoside compound has a goodeffect of treating inflammatory bowel diseases, particularly ulcerativecolitis.

The present invention provides a compound represented by formula A-1, apharmaceutically acceptable salt thereof, a solvate thereof, or acrystal form thereof,

wherein R¹, R², R³, and R⁴ are independently hydrogen, C₁₋₄ alkyl,benzyl, —C(=O)R, or —C(═O)—O—R′, and R¹, R², R³, and R⁴ are notsimultaneously hydrogen;

each R¹ is independently C₁₋₄ alkyl;

each R is independently C₁₋₄ alkyl or phenyl;

R⁵ and R⁶ are independently hydrogen, or R⁵ and R⁶ are taken together toform ═O;

R⁸ and R⁹ are independently C₁₋₄ alkyl;

alternatively, R⁸ and R⁹ are taken together with the carbon atom towhich they are attached to form 3- to 7-membered cycloalkyl, 3- to7-membered heterocycloalkyl, 3- to 7-membered cycloalkyl substitutedwith one or a plurality of R^(a), or 3- to 7-membered heterocycloalkylsubstituted with one or a plurality of R^(b); in the 3- to 7-memberedheterocycloalkyl and the 3- to 7-membered heterocycloalkyl substitutedwith one or a plurality of R^(b), the heteroatoms in the 3- to7-membered heterocycloalkyl are independently selected from N, O, and S,and the number of heteroatoms is independently 1, 2, or 3;

R^(a) and R^(b) are independently C₁₋₄ alkyl, —C(═O)R″;

each R″ is independently C₁₋₄ alkyl;

carbon atoms marked with “*” indicate that when the carbon atoms arechiral, the carbon atoms are in the R-configuration, S-configuration, ora mixture of R-configuration and S-configuration.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, certain groups are defined as follows (undefined groups are thesame as above), when R¹, R², R³, and R⁴ are independently C₁₋₄ alkyl,then C₁₋₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, or tert-butyl; preferably methyl.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, each R′ is independently methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably ethyl.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, when each R is independently C₁₋₄ alkyl, then C₁₋₄ alkyl ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ortert-butyl; preferably methyl or tert-butyl.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, when R⁸ and R⁹ are independently C₁₋₄ alkyl, then C₁₋₄ alkyl ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ortert-butyl; preferably methyl.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, when R⁸ and R⁹ are taken together with the carbon atom to whichthey are attached to form 3- to 7-membered cycloalkyl or 3- to7-membered cycloalkyl substituted with one or a plurality of R^(a), then3- to 7-membered cycloalkyl is a 5- to 6-membered cycloalkyl.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, when R⁸ and R⁹ are taken together with the carbon atom to whichthey are attached to form 3- to 7-membered heterocycloalkyl or 3- to7-membered heterocycloalkyl substituted with one or a plurality ofR^(b), in the 3- to 7-membered heterocycloalkyl, then in the 3- to7-membered heterocycloalkyl, the heteroatoms are independently selectedfrom N and O, and the number of heteroatoms is independently 1.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, when R⁸ and R⁹ are taken together with the carbon atom to whichthey are attached to form 3- to 7-membered heterocycloalkyl or 3- to7-membered heterocycloalkyl substituted with one or a plurality ofR^(b), wherein the 3- to 7-membered heterocycloalkyl is 5- to 6-memberedheterocycloalkyl.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, when R⁸ and R⁹ are taken together with the carbon atom to whichthey are attached to form 3- to 7-membered heterocycloalkyl, then

is

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, when R^(a) and R^(b) are independently C₁₋₄ alkyl, then C₁₋₄alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, or tert-butyl.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, each R″ is independently methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably methyl.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, when R⁸ and R⁹ are taken together with the carbon atom to whichthey are attached to form 3- to 7-membered heterocycloalkyl substitutedwith one or a plurality of R^(b), then

is

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, R¹, R², R³, and R⁴ are independently hydrogen, C₁₋₄ alkyl,—C(═O)R, or —C(═O)—O—R′.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, R¹ is C₁₋₄ alkyl, —C(═O)R, or —C(═O)—O—R′; preferably C₁₋₄alkyl or —C(═O)R.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, R¹ is methyl,

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, R², R³, and R⁴ are independently hydrogen or —C(═O)R;preferably, R², R³, and R⁴ are independently —C(═O)R.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, R², R³, and R⁴ are independently hydrogen,

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, R², R³, and R⁴ are the same group.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, when R⁵ and R⁶ are independently hydrogen, then R¹ is —C(═O)R

or —C(═O)—O—R′

when R⁵ and R⁶ are taken together to form ═O, then R¹ is C₁₋₄ alkyl(e.g., methyl).

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, each R is independently C₁₋₄ alkyl; preferably methyl ortert-butyl.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, R^(a) and R^(b) are independently —C(═O)R″; preferably

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, R⁸ and R⁹ are independently C₁₋₄ alkyl, or R⁸ and R⁹ are takentogether with the carbon atom to which they are attached to form 3- to7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or 3- to7-membered heterocycloalkyl substituted with one or a plurality ofR^(b); preferably, R⁸ and R⁹ are independently C₁₋₄ alkyl, or R⁸ and R⁹are taken together with the carbon atom to which they are attached toform 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl.

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof,

In a certain embodiment of the present invention,

is

preferably

or a mixture of

in a molar ratio of 1:1).

In the compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof, the structure of the compound represented by formula A-1 is asfollows:

wherein R¹, R², R³, and R⁴ are independently hydrogen, C₁₋₄ alkyl,benzyl, or —C(═O)R, and R¹, R², R³, and R⁴ are not simultaneouslyhydrogen;

each R is independently C₁₋₄ alkyl or phenyl.

In the compound represented by formula A, certain groups are defined asfollows (undefined groups are the same as above), preferably, R¹, R²,R³, and R⁴ are independently hydrogen or —C(═O)R.

In the compound represented by formula A, certain groups are defined asfollows (undefined groups are the same as above), preferably, each R isindependently C₁₋₄ alkyl.

In the compound represented by formula A, preferably, R¹, R², R³, and R⁴are hydrogen or —C(═O)R, each R is independently C₁₋₄ alkyl.

In the compound represented by formula A, when R¹, R², R³, and R⁴ areindependently C₁₋₄ alkyl, then C₁₋₄ alkyl is preferably methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

In the compound represented by formula A, preferably, each R isindependently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, or phenyl, more preferably methyl.

In the compound represented by formula A, preferably, R¹, R², R³, and R⁴are the same group.

The structure of the compound represented by formula A can be asfollows:

or a mixture of

in a molar ratio of 1:1, the preferred structure is

The compound represented by formula A-1 can be any of the followingcompounds,

The present invention provides a pharmaceutical composition comprisingthe compound represented by formula A-1, the pharmaceutically acceptablesalt thereof, the solvate thereof or the crystal form thereof, and apharmaceutical adjuvant;

the structure of the compound represented by formula A-1 is as follows:

wherein R¹, R², R³, and R⁴ are independently hydrogen, C₁₋₄ alkyl,benzyl, —C(═O)R, or —C(═O)—O—R′;

R, R′, *, R⁵, R⁶, R⁸, and R⁹ are defined in any of previous embodimentsabove.

The pharmaceutical composition is preferably a pharmaceuticalcomposition for treating inflammatory bowel diseases. The inflammatorybowel disease is preferably ulcerative colitis.

The present invention provides use of a compound represented by formulaA-1, a pharmaceutically acceptable salt thereof, a solvate thereof, acrystal form thereof, or the above-mentioned pharmaceutical compositionin the preparation of a medicament. The medicament is preferably amedicament for treating inflammatory bowel disease, more preferably fortreating ulcerative colitis;

the structure of the compound represented by formula A-1 is as follows:

wherein R¹, R², R³, and R⁴ are independently hydrogen, C₁₋₄ alkyl,benzyl, —C(=O)R, or —C(═O)—O—R′;

R, R′, *, R⁵, R⁶, R⁸, and R⁹ are defined in any of the previousembodiments.

In the pharmaceutical composition or the use, certain groups are definedas follows (undefined groups are the same as above), when R¹, R², R³,and R⁴ are independently C₁₋₄ alkyl, then C₁₋₄ alkyl is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;preferably methyl.

In the pharmaceutical composition or the use, certain groups are definedas follows (undefined groups are the same as above), R¹, R², R³, and R⁴are independently hydrogen, C₁₋₄ alkyl, —C(═O)R, or —C(═O)—O—R′.

In the pharmaceutical composition or the use, certain groups are definedas follows (undefined groups are the same as above), R¹ is C₁₋₄ alkyl,—C(═O)R, or —C(═O)—O—R′; preferably C₁₋₄ alkyl or —C(═O)R.

In the pharmaceutical composition or the use, certain groups are definedas follows (undefined groups are the same as above), R¹ is methyl,

In the pharmaceutical composition or the use, certain groups are definedas follows (undefined groups are the same as above), R², R³, and R⁴ areindependently hydrogen or —C(═O)R; preferably, R², R³, and R⁴ areindependently —C(═O)R.

In the pharmaceutical composition or the use, certain groups are definedas follows (undefined groups are the same as above), R², R³, and R⁴ areindependently hydrogen,

In the pharmaceutical composition or the use, certain groups are definedas follows (undefined groups are the same as above), R², R³, and R⁴ arethe same group.

In the pharmaceutical composition or the use, certain groups are definedas follows (undefined groups are the same as above), when R⁵ and R⁶ areindependently hydrogen, then R¹ is —C(═O)R

or —C(═O)—O—R′

when R⁵ and R⁶ are taken together to form ═O, then R¹ is C₁₋₄ alkyl(e.g., methyl).

In the pharmaceutical composition or the use, preferably,

is

more preferably

or a mixture of

in a molar ratio of 1:1).

In the pharmaceutical composition or the use, certain groups are definedas follows (undefined groups are the same as above), the structure ofthe compound represented by formula A-1 is as follows:

wherein R¹, R², R³, and R⁴ are independently hydrogen, C₁₋₄ alkyl,benzyl, or —C(═O)R;

R is defined in any of previous embodiments above.

In the pharmaceutical composition or the use, certain groups are definedas follows (undefined groups are the same as above), preferably, R¹, R²,R³, and R⁴ are independently hydrogen or —C(═O)R.

In the pharmaceutical composition or the use, preferably, R¹, R², R³,and R⁴ are independently hydrogen or —C(═O)R, each R is independentlyC₁₋₄ alkyl.

In the pharmaceutical composition or the use, when R¹, R², R³, and R⁴are independently C₁₋₄ alkyl, then C₁₋₄ alkyl is preferably methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In the pharmaceutical composition or the use, preferably, R¹, R², R³,and R⁴ are the same group.

In the pharmaceutical composition or the use, the structure of thecompound represented by formula A can be as follows:

or a mixture of

in a molar ratio of 1:1, the preferred structure is

In the pharmaceutical composition or the use, the compound representedby formula A-1 can be any of the following compounds:

The present invention provides a crystal form of the compoundrepresented by formula I-2,

the unit cell parameters of the compound represented by formula I-2 are:a=10.5391(3) Å, α=90°; b=14.2167(4) Å, β=90°; c=15.9116(5) Å, γ=90°;space group P2₁2₁2₁; preferably:

Empirical formula C₂₂H₂₈O₁₂ Formula weight 484.44 Temperature 169.99 KWavelength 1.34139 Å Crystal system Orthorhombic system Space groupP2₁2₁2₁ Unit cell dimensions a = 10.5391(3) Å, α = 90° b = 14.2167(4) Å,β = 90° c = 15.9116(5) Å, γ = 90° Unit cell volume 2384.05(12) Å³ Z 4Density (calculated) 1.350 Mg/m³ Absorption coefficient 0.607 mm⁻¹F(000) 1024 Crystal size 0.12 × 0.1 × 0.05 mm³ Theta range for 5.148 to54.935° data collection Index ranges −12 <= h <= 12, −15 <= k <= 17, −19<= l <= 19 Reflections collected 21844 Independent reflections 4478[R(int) = 0.0451] Refinement method Full-matrix least-squares on F²

The present invention provides a pharmaceutical composition comprising acrystal form of the compound represented by formula I-2 and apharmaceutical adjuvant. The pharmaceutical composition is preferably apharmaceutical composition for treating inflammatory bowel disease,wherein the inflammatory bowel disease is preferably ulcerative colitis.

The present invention provides use of the crystal form of the compoundrepresented by formula I-2 or the pharmaceutical composition in thepreparation of a medicament. The medicament is preferably a medicamentfor treating inflammatory bowel disease, more preferably for treatingulcerative colitis.

The present invention provides a method of preparing the compoundrepresented by formula A-1, comprising the steps of any of the followingmethods:

Method A:

in a solvent, in the presence of a catalyst, a compound represented byformula B-1 and a compound represented by formula C-1 are subjected toan ether-forming reaction shown below to obtain the compound representedby formula A-1;

in the method A, R¹, R², R³, and R⁴ are independently C₁₋₄ alkyl,benzyl, —C(═O)R, or —C(═O)—O—R′;

R, R′, *, R⁵, R⁶, R⁸, and R⁹ are defined in any of the previousembodiments;

Method B:

in a solvent, a compound represented by formula D-1 and a compoundrepresented by formula E-1 are subjected to a reaction shown below toobtain the compound represented by formula A-1;

in the method B, R¹, R², R³, and R⁴ are independently C₁₋₄ alkyl,benzyl, —C(═O)R, or —C(═O)—O—R′; R⁸ and R⁹ are independently C₁₋₄ alkyl;

R, R′, *, R⁵, and R⁶ are defined in any of the previous embodiments;

Method C:

in a solvent, in the presence of a base, a compound represented byformula F-1 is subjected to a hydrolysis reaction shown below to obtainthe compound represented by formula A-1;

in the method C, R¹, R², R³, and R⁴ are hydrogen;

R, *, R⁵, R⁶, R⁸, and R⁹ are defined in any of the previous embodiments;

Method D:

in a solvent, in the presence of a catalyst, a compound represented byformula G-1 and a compound represented by formula G-2 are subjected to asubstitution reaction shown below to obtain the compound represented byformula A-1;

in the method D, R², R³, and R⁴ are hydrogen;

R′, *, R⁵, R⁶, R⁸, and R⁹ are defined in any of the previousembodiments.

In a certain embodiment, in the method A, the conditions and operationsof the ether-forming reaction can be conventional conditions andoperations of this type of reaction in the art.

In a certain embodiment, in the method B, the conditions and operationsof the reaction can be conventional conditions and operations of thistype of reaction in the art.

In a certain embodiment, in the method C, the conditions and operationsof the hydrolysis reaction can be conventional conditions and operationsof this type of reaction in the art.

In a certain embodiment, in the method D, the conditions and operationsof the substitution reaction can be conventional conditions andoperations of this type of reaction in the art.

In a certain embodiment, the described method A includes the followingsteps: in the solvent, in the presence of the catalyst, a compoundrepresented by formula B and a compound represented by formula C aresubjected to the ether-forming reaction shown below to obtain a compoundrepresented by formula I-3;

wherein R is defined in any of the embodiments.

In a certain embodiment, the described method B includes the followingsteps: in the solvent, a compound represented by formula D and acetoneare subjected to the reaction shown below to obtain the compoundrepresented by formula I-3;

wherein R is defined in any of the previous embodiments.

In a certain embodiment, the described method C includes the followingsteps: in the solvent, in the presence of the base, the compoundrepresented by formula I-3 is subjected to the hydrolysis reaction shownbelow to obtain the compound represented by formula I-1;

wherein R is defined in any of the previous embodiments.

The present invention provides a method of treating inflammatory boweldisease comprising administrating a therapeutically effective amount ofsubstance A to a patient;

the substance A comprises the compound represented by formula A-1, thepharmaceutically acceptable salt thereof, the solvate thereof, thecrystal form thereof, or the pharmaceutical composition thereof;

wherein the compound represented by formula A-1 is the same as anyembodiment of the compound represented by formula A-1 in thepharmaceutical composition.

In the method of treating inflammatory bowel disease, the inflammatorybowel disease is preferably ulcerative colitis.

Unless otherwise specified, the terms used in the present inventionshall have the following meanings:

Those skilled in the art can understand that, according to theconventions used in the art, the

used in the structural formula of the group means that the correspondinggroup is connected to other fragments or groups in the compound throughthis site.

As used herein, the term “plurality” refers to 2, 3, 4, or 5, preferably2 or 3.

When any variable (e.g., R^(b)) appears multiple times in the definitionof a compound, the definition that appears at each position of thevariable is independent of the definitions that appear at otherpositions, and their meanings are independent of each other and do notaffect each other. Thus, if a group is substituted with 1, 2, or 3 R^(b)groups, the group may be substituted with up to 3 R^(b) groups, thedefinition of R^(b) at that position is independent of the definition ofR^(b) at the remaining positions. Additionally, the combination ofsubstituents and/or variables is permissible only if the combinationproduces a stable compound.

The pharmaceutical adjuvants described in the present invention can bethose widely used in the field of pharmaceutical production. Adjuvantsare primarily used to provide a safe, stable, and functionalpharmaceutical composition, and may also provide methods to enable theactive ingredient to dissolve at a desired rate after the subject hasreceived administration or to facilitate effective absorption of theactive ingredient after the subject has received administration of thecomposition. The pharmaceutical adjuvants can be inert fillers orprovide some function, such as stabilizing the overall pH of thecomposition or preventing degradation of the active ingredients of thecomposition. The pharmaceutical adjuvants may include one or more of thefollowing adjuvants: binder, suspending agent, emulsifying agent,diluting agent, stuffing bulking agent, granulating agent, adhesiveagent, disintegrating agent, lubricant, anti-adhesive agent, flow aid,wetting agent, gelling agent, absorption retardant, dissolutioninhibitor, enhancer, adsorbent, buffering agent, chelating agent,preservative, coloring agent, flavoring agent, and sweetening agent.

The pharmaceutical compositions of the present invention can be preparedaccording to the disclosure using any method known to those skilled inthe art. For example, conventional mixing, dissolving, granulating,emulsifying, levigating, encapsulating, embedding, or lyophilizingprocesses.

The pharmaceutical compositions of the present invention can beadministered in any form, including injection (intravenous), mucosal,oral (solid and liquid preparations), inhalation, ophthalmic, rectal,topical, or parenteral (infusion, injection, implant, subcutaneous,intravenous, intraarterial, intramuscular) administration. Thepharmaceutical compositions of the present invention may also be incontrolled-release or delayed-release forms (e.g., liposomes ormicrospheres). Examples of solid oral preparations include, but are notlimited to, powders, capsules, caplets, softgels, and tablets, such asenteric-coated tablets or capsules. Examples of liquid preparations fororal or mucosal administration include, but are not limited to,suspensions, emulsions, elixirs, and solutions. Examples of topicalpreparations include, but are not limited to, emulsions, gels,ointments, creams, patches, pastes, foams, lotions, drops, or serumpreparations. Examples of preparations for parenteral administrationinclude, but are not limited to, solutions for injection, drypreparations that can be dissolved or suspended in a pharmaceuticallyacceptable vehicle, suspensions for injection and emulsions forinjection. Examples of other suitable preparations of the pharmaceuticalcomposition include, but are not limited to, eye drops and otherophthalmic preparations; aerosols: such as nasal sprays or inhalants;liquid preparations for parenteral administration; suppositories andlozenges.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt of a compound of the present invention prepared with a relativelynon-toxic, pharmaceutically acceptable acid or base. When the compoundsof the present invention contain relatively acidic functional groups,base addition salts can be formed by contacting the neutral forms ofsuch compounds with a sufficient amount of a pharmaceutically acceptablebase in a neat solution or a suitable inert solvent. Thepharmacologically acceptable base addition salts include, but are notlimited to lithium, sodium, potassium, calcium, aluminum, magnesium,zinc, bismuth, ammonium, diethanolamine salts. When the compounds of thepresent invention contain relatively basic functional groups, acidaddition salts can be formed by contacting the neutral forms of suchcompounds with a sufficient amount of a pharmaceutically acceptable acidin a neat solution or a suitable inert solvent. The pharmaceuticallyacceptable acids include inorganic acids, including but not limited to:hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc.The pharmaceutically acceptable acids include organic acids, includingbut not limited to: acetic acid, propionic acid, oxalic acid, isobutyricacid, maleic acid, malonic acid, benzoic acid, succinic acid,octanedioic acid, (E)-butenedioic acid, lactic acid, mandelic acid,phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citricacid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinicacid, acid citric acid, oleic acid, tannic acid, pantothenic acid,tartaric acid hydrogen, ascorbic acid, gentianic acid, fumaric acid,gluconic acid, glycolic acid, formic acid, pamoic acid (i.e.,4,4′-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g.,glutamic acid, arginine), etc. When the compounds of the presentinvention contain relatively acidic and relatively basic functionalgroups, they can be converted into base addition salts or acid additionsalts. For details, refer to Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science 66: 1-19 (1977), or, Handbook ofPharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahland Camille G. Wermuth, ed., Wiley-VCH, 2002).

As used herein, the term “solvate” refers to a substance formed bycombining a compound of the present invention with a stoichiometric ornon-stoichiometric amount of a solvent. Solvent molecules in solvatescan exist in ordered or non-ordered arrangements. The solvent includesbut is not limited to, water, methanol, ethanol, etc.

As used herein, the term “crystal form” refers to that the ions ormolecules are arranged in a definite, repeating pattern inthree-dimension space and have the regularity of periodic arrangement ata certain distance. Due to the differences in the periodic arrangementof ions or molecules, more than one crystal form can exist, i.e.,polymorphism.

As used herein, the term “treatment” refers to therapeutic therapy.Concerning a specific condition, treatment refers to: (1) alleviatingone or more biological manifestations of a disease or condition, (2)interfering with (a) one or more points in the biological cascadeleading to or causing the condition, or (b) one or more biologicalmanifestations of the condition, (3) ameliorating one or more symptoms,effects, or side effects associated with the condition, or one or moresymptoms, effects, or side effects associated with the condition or thetreatment, or (4) slowing the development of the condition or one ormore biological manifestations of the condition.

As used herein, the term “therapeutically effective amount” refers to anamount of a compound that, when administered to a patient, is sufficientto effectively treat the disease or condition described herein. A“therapeutically effective amount” will vary depending on the compound,the condition, the severity of the condition, and the age of the patientto be treated, but can be adjusted as needed by those skilled in theart.

As used herein, the term “patient” refers to any animal, preferably amammal, and most preferably a human, which is about to receive or hasreceived the compound or composition according to an example of thepresent invention. The term “mammal” includes any mammal. Examples ofmammals include, but are not limited to, cows, horses, sheep, pigs,cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.,with humans being the most preferred.

Based on not violating common knowledge in the art, the preferredconditions above can be combined arbitrarily to obtain examples of thepresent invention.

The reagents and raw materials used in the present invention are allcommercially available.

The positive effect of the invention is that the furaneol glycosidecompound has a good therapeutic effect on inflammatory bowel disease,particularly ulcerative colitis.

DESCRIPTION OF FIGURES

FIG. 1 is the crystal structure of compound I-2.

FIG. 2 is the colons morphology of the mice in each group in effectexample 1.

MODE OF CARRYING OUT THE INVENTION

The present invention is further described below by way of examples, butthe present invention is not limited to the scope of the describedexamples. The experimental methods that do not specify specificconditions in the following examples are selected according toconventional methods and conditions, or according to the productoperation instruction.

EXAMPLE 1

Step 1: 4-Hydroxy-5-methyl-3(2H)-furanone (1.14 g, 10 mmol, CAS:19322-27-1), copper acetate (905 mg, 5 mmol), and sodium acetate (680mg, 5 mmol) were dissolved in 10 mL of acetone and 30 mL of glacialacetic acid, heated to 50° C., stirred and refluxed for 1 hour; thendiluted with 150 mL of water, and extracted the product with 100 mL ofpetroleum ether. the crude product was concentrated and chromatographedon silica gel (ethyl acetate/petroleum ether: ½) to give4-hydroxy-5-methyl-2-(1-methylethylidene)-3(2H)-furanone (1.23 g, 80%yield). ¹H NMR (400 MHz, CD₃OD) δ(ppm): 2.36 (s, 3H), 2.31 (s, 3H), 2.05(s, 3H). ESI-MS: 155 [M+1]⁺.

Step 2: 4-Hydroxy-5-methyl-2-(1-methylethylidene)-3(2H)-furanone (1.54g, 10 mmol), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (6.15 g,15 mmol, CAS: 572-09-8), and tetrabutylammonium bromide (4.83 g, 15mmol, CAS: 1643-19-2) were dissolved in 50 mL of dichloromethane andheated to 35° C.; 75 mL of NaOH aqueous solution (1 mol/L) was furtheradded. After stirring for 45 minutes, 300 mL of ethyl acetate was addedto extract the organic phase; the organic phase was washed three timeswith NaOH aqueous solution (1 mol/L), twice with water, and once withbrine; the crude product was concentrated and chromatographed on silicagel (ethyl acetate/petroleum ether: 1/1) to give 4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-glucosyl]-5-methyl-2-(1-methylethylidene)-3(2H)-furanone asa white solid (0.97 g, 20% yield, compound I-2). ¹H NMR (400 MHz, CDCl₃)δ (ppm): 5.24-5.07 (m, 4H), 4.20 (br d, J=12.3 Hz, 1H), 4.11 (br d,J=12.2 Hz, 1H), 3.68 (m, 1H), 2.25 (s, 3H), 2.19 (s, 3H), 2.11 (s, 3H),2.04 (s, 3H), 1.99 (s, 6H), 1.97 (s, 3H). ¹³C NMR (100 MHz, CDCl₃)δ(ppm): 179.24, 170.67, 170.21, 170.01, 169.63, 168.30, 143.18, 135.65,133.01, 99.75, 72.78, 72.01, 71.23, 68.52, 61.82, 20.94, 20.80, 20.74,19.52, 17.25, 12.62. ESI-MS: 485 [M+1]⁺.

Cultivation of single crystal: Compound I-2 (10 mg) was dissolved inanhydrous methanol (10 mL), water (4 mL) was added. After filtered, thefiltrate was transferred to a 100 mL single-neck conical flask, andallowed to stand at 0-4° C. for 1-3 days. The single crystal wasprecipitated and collected for single crystal X-ray diffraction.

The configuration of compound I-2 was determined by crystal X-raydiffraction, the crystal form of compound I-2 was as described in thecontents of the present invention, and the crystal structure of compoundI-2 was shown in FIG. 1 .

Step 3:4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-glucosyl]-5-methyl-2-(1-methylethylidene)-3(2H)-furanone(4.69 g, 10 mmol) was dissolved in 100 mL of methanol and sodiumcarbonate (5.3 g, 50 mmol) was added. After stirring for 4 h at roomtemperature, the crude product was concentrated after filtration andchromatographed on a C18-bonded silica gel (methanol, 50% (v/v) aqueoussolution) to give Phoenicein[4-O-β-D-glucosyl-5-methyl-2-(1-methylethylidene)-3(2H)-furanone] as anoff-white solid (1.90 g, 60% yield, Compound I-1). ¹H NMR (400 MHz,CD₃OD) δ (ppm): 4.74 (d, J=7.8 Hz, 1H), 3.84 (dd, J =12.0, 2.1 Hz, 1H),3.69 (dd, J=12.0, 5.1 Hz, 1H), 3.45-3.27 (m, 4H), 2.35 (s, 3H), 2.30 (s,3H), 2.05 (s, 3H). ESI-MS: 317 [M+1]⁺.

EXAMPLE 2

Step 1: 4-Hydroxy-5-methyl-3(2H)-furanone (1.14 g, 10 mmol, CAS:19322-27-1), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (8.2 g,20 mmol, CAS: 572-09-8), and tetrabutylammonium bromide (4.83 g, 15mmol, CAS: 1643-19-2) were dissolved in 60 mL of dichloromethane andheated to 35° C.; 80 mL of aqueous NaOH (1 mol/L) was further added.After stirring for 45 minutes, 300 mL of ethyl acetate was added toextract the organic phase; the organic phase was washed three times withaqueous NaOH (1 mol/L), twice with water and once with brine; the crudeproduct was concentrated and chromatographed on silica gel (ethylacetate/petroleum ether: 1/1) to give4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-glucosyl]-5-methyl-3(2H)-furanone as awhite solid (0.67 g, 15% yield). ¹H NMR (400 MHz, CDCl₃) δ 5.24 (m, 1H),5.12 (m, 3H), 4.48 (s, 2H), 4.23 (dd, J=12.2, 3.5 Hz, 1H), 4.15 (dd,J=12.5, 1.9 Hz, 1H), 3.72 (m, 1H), 2.24 (s, 3H), 2.12 (s, 3H), 2.07 (s,3H), 2.02 (s, 6H). ESI-MS: 445 [M+1]⁺.

Step 2:4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-glucosyl]-5-methyl-3(2H)-furanone(4.44 g, 10 mmol), copper acetate (905 mg, 5 mmol), and sodium acetate(680 mg, 5 mmol) were dissolved in 10 mL acetone and 30 mL glacialacetic acid, heated to 50° C., stirred and refluxed for 1 hour; thendiluted with 150 mL of water, and extracted with 100 mL of petroleumether; the crude product was concentrated and chromatographed on silicagel (ethyl acetate/petroleum ether: 1/1) to give4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-glucosyl]-5-methyl-2-(1-methylethylidene)-3(2H)-furanoneas a white solid (1.94 g, 40% yield, Compound I-2).

EXAMPLE 3

4-Hydroxy-5-methyl-2-(1-methylethylidene)-3(2H)-furanone (1.54 g, 10mmol), 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (6.15 g, 15mmol), and tetrabutylammonium bromide (4.83 g, 15 mmol, CAS: 1643-19-2)were dissolved in 60 mL of dichloromethane and heated to 35° C.; 75 mLof NaOH aqueous solution (1 mol/L) was further added. After stirring for45 minutes, 300 mL of ethyl acetate was added to extract the organicphase; the organic phase was washed three times with NaOH aqueoussolution (1 mol/L), twice with water, and once with brine; the crudeproduct was concentrated and chromatographed on silica gel (ethylacetate/petroleum ether: 1/1) to give4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-galactosyl]-5-methyl-2-(1-methylethylidene)-3(2H)-furanoneas a white solid (2.31 g, 48% yield, compound I-4).

I-4: ¹H NMR (400 MHz, CDCl₃): δ 5.40 (d, J=2.7 Hz, 1H), 5.33 (dd,J=10.5, 8.0 Hz, 1H), 5.08 (d, J=8.0 Hz, 1H), 5.04 (dd, J=10.5, 3.5 Hz,1H), 4.11 (m, 2H), 3.89 (t, J=6.7 Hz, 1H), 2.27 (s, 3H), 2.22 (s, 3H),2.16 (s, 3H), 2.15 (s, 3H), 2.01 (s, 3H), 1.99 (s, 6H). ¹³C NMR (100MHz, CDCl₃): δ 179.36, 170.47, 170.38, 170.27, 170.15, 168.42, 143.18,135.94, 132.99, 100.72, 71.02, 70.85, 68.74, 67.01, 61.15, 21.08, 20.81,20.76, 20.71, 19.51, 17.25, 12.70. ESI-MS: 485 [M+1]⁺.

EXAMPLE 4

Compound I-5 was prepared using a similar method to example 3.

I-5: ¹H NMR (400 MHz, CDCl₃) δ 5.31 (d, J=9.3 Hz, 1H), 5.27 (t, J=7.9Hz, 1H), 5.21 (t, J=9.6 Hz, 1H), 5.16 (dd, J=9.2, 7.9 Hz, 1H), 4.02 (d,J=9.8 Hz, 1H), 3.72 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 2.12 (s, 3H),2.02 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ179.18, 170.02, 169.91, 169.66, 168.75, 167.12, 143.20, 135.39, 133.25,99.40, 72.41, 72.00, 71.01, 69.54, 52.95, 20.90, 20.73, 20.62, 19.53,17.26, 12.70. ESI-MS: 471 [M+1]⁺.

EXAMPLE 5

Compound I-6 was prepared using a similar method to example 3.

I-6: ¹H NMR (400 MHz, CDCl₃) δ 5.34 (t, J=8.0 Hz, 1H), 5.30 (d, J=8.0Hz, 1H), 5.16 (t, J=8.0 Hz, 1H), 5.14 (m, 1H), 4.17 (dd, J=12.2, 1.7 Hz,1H), 4.02 (dd, J=12.3, 5.5 Hz, 1H), 3.70 (ddd, J=10.0, 5.4, 1.7 Hz, 1H),2.25 (s, 3H), 2.18 (s, 3H), 1.97 (s, 3H), 1.19 (s, 9H), 1.16 (s, 9H),1.14 (s, 9H), 1.12 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 179.05, 178.03,177.20, 177.17, 176.66, 168.60, 143.19, 135.02, 132.56, 99.03, 72.43,72.22, 71.25, 68.01, 61.69, 38.99, 38.93, 38.92, 38.85, 27.28(×3),27.22(×3), 27.18(×3), 27.12(×3), 19.44, 17.23, 12.60. ESI-MS: 653[M+1]⁺.

EXAMPLE 6

I-1 (316 mg, 1 mmol) was dissolved in toluene-ethanol (4:1, 30 mL)solution, Sc(OTF)3 (7.38 mg, 0.015 mmol) and DEPC (186 mg, 1.15 mmol)were added. The solution was heated to 50° C. for 2 h, then quenchedwith dilute acetic acid (2.5%, 3.75 mL). The mixture was cooled to 20°C. and the aqueous layer was discarded, the organic layer was washedagain with dilute acetic acid (2.5%, 3.75 mL), and the aqueous layer wasdiscarded. The final organic layer was then concentrated andchromatographed on silica gel (dichloromethane/methanol: 10/1) to givecompound I-7 (210 mg, 54% yield).

I-7: ¹H NMR (400 MHz, CDCl₃) δ 4.70 (d, J=8.1 Hz, 1H), 4.44 (d, J=11.0Hz, 1H), 4.32 (dd, J=11.7, 5.7 Hz, 1H), 4.17 (m, 2H), 3.70-3.51 (m, 2H),3.41 (t, J=9.3 Hz, 1H), 3.29 (t, J=8.6 Hz, 1H), 2.27 (s, 3H), 2.24 (s,3H), 2.05 (s, 3H), 1.29 (t, J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ181.73, 171.69, 155.41, 143.22, 136.00, 134.72, 103.13, 75.81, 74.40,72.07, 69.77, 66.73, 64.34, 19.73, 17.70, 14.37, 13.11. ESI-MS: 389[M+1]⁺.

EXAMPLE 7

4-Hydroxy-5-methyl-2-cyclopentyl-3(2H)-furanone (1.80 g, 10 mmol),2,3,4,6-tetra-O -acetyl-α-D-glucopyranosyl bromide (6.15 g, 15 mmol,CAS: 572-09-8), and tetrabutylammonium bromide (4.83 g, 15 mmol, CAS:1643-19-2) were dissolved in 60 mL of dichloromethane and heated to 35°C.; 75 mL of NaOH aqueous solution (1 mol/L) was further added. Afterstirring for 45 minutes, 300 mL of ethyl acetate was added to extractthe organic phase; the organic phase was washed three times with NaOHaqueous solution (1 mol/L), twice with water, and once with brine; thecrude product was concentrated and chromatographed on silica gel (ethylacetate/petroleum ether: 1/1) to give4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-glucosyl]-5-methyl-2-cyclopentyl-3(2H)-furanoneas a white solid (2.51 g, 49% yield, compound I-8).

I-8: ¹H NMR (400 MHz, CDCl₃): δ 5.21-5.26 (m, 2H), 5.10-5.17 (m, 2H),4.23 (dd, J=12.4, 4.4 Hz, 1H), 4.14 (dd, J=12.4, 2.4 Hz, 1H), 3.70 (m,1H), 2.84 (t, J=6.6 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.22 (s, 3H), 2.13(s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 1.80 (m, 4H). ¹³C NMR(100 MHz, CDCl₃) δ 178.81, 170.69, 170.22, 170.02, 169.64, 168.68,143.01, 140.87, 135.46, 99.68, 72.76, 71.95, 71.19, 68.45, 61.77, 31.05,30.24, 26.80, 25.43, 20.96, 20.83, 20.75(×2), 12.72. ESI-MS: 511 [M+1]⁺.

EXAMPLE 8

Compound I-9 was prepared using a similar method to example 7.

I-9: H NMR (400 MHz, CDCl₃) δ 5.23 (t, J=8.5 Hz, 1H), 5.19-5.05 (m, 3H),4.22 (dd, J=12.4, 7.6 Hz, 1H), 4.14 (dd, J=12.4, 2.4 Hz, 1H), 3.69 (m,1H), 2.94 (t, J=5.8 Hz, 2H), 2.43 (t, J=6.0 Hz, 2H), 2.20 (s, 3H), 2.13(s, 3H), 2.06 (s, 3H), 2.02 (s, 6H), 1.66 (m, 6H). ¹³C NMR (100 MHz,CDCl₃) δ 179.80, 170.69, 170.23, 170.04, 169.65, 168.42, 140.96, 140.61,135.83, 99.85, 72.73, 71.94, 71.18, 68.48, 61.79, 28.69, 27.87, 27.61,26.27, 26.12, 20.97, 20.83, 20.76(×2), 12.66. ESI-MS: 525 [M+1]⁺.

EXAMPLE 9

Compound I-10 was prepared using a similar method to example 7.

I-10: ¹H NMR (400 MHz, CDCl₃): δ 5.24 (t, J=6.4 Hz, 1H), 5.13 (m, 3H),4.21 (dd, J=12.4, 5.6 Hz, 1H), 4.15 (dd, J=12.0, 2.4 Hz, 1H), 3.80 (m,4H), 3.69 (m, 1H), 3.11 (m, 2H), 2.58 (t, J=5.6 Hz, 2H), 2.22(s, 3H),2.13 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H). ¹³C NMR (100MHz, CDCl₃) δ 179.82, 170.65, 170.22, 169.98, 169.62, 169.15, 140.89,135.80, 133.88, 99.86, 72.68, 72.00, 71.15, 68.55, 68.43, 68.10, 61.75,28.91, 26.93, 20.94, 20.83, 20.75(×2), 12.72. ESI-MS: 527 [M+1]⁺.

EXAMPLE 10

Compound I-11 was prepared using a similar method to example 7.

I-11: ¹H NMR (400 MHz, CDCl₃) δ 9.81 (s, N—H), 5.24 (t, J=8.9 Hz, 1H),5.13 (m, 3H), 4.19 (m, 2H), 3.70 (m, 1H), 3.52-3.16 (m, 6H), 2.91 (br s,2H), 2.24 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 2.01 (s,3H). ¹³C NMR (100 MHz, CDCl₃) 6179.79, 170.65, 170.55, 170.23, 169.92,169.61, 141.48, 135.77, 126.60, 99.94, 72.60, 72.08, 71.10, 68.32,61.68, 44.43(×2), 24.25, 21.85, 20.93, 20.87, 20.75(×2), 12.85. ESI-MS:526 [M+1]⁺.

EXAMPLE 11

Compound I-12 was prepared using a similar method to example 7.

I-12: ¹H NMR (400 MHz, CDCl₃): δ 5.10-5.27 (m, 4H), 4.11-4.25 (m, 2H),3.73 (m, 4H), 3.56 (m, 1H), 3.10 (m, 2H), 2.58 (m, 2H), 2.24(s, 3H),2.15 (s, 3H), 2.13 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H).ESI-MS: 568 [M+1]⁺.

Effect Example 1: Therapeutic Effect of Compound I-1 on UlcerativeColitis

1. Experimental Procedure

1.1 Experimental Animals and Experimental Conditions

Thirty 10-week-old male C57 mice, SPF class animal house, temperature20-26° C., humidity 40%-70%, alternating light-dark periods (12 h/12 h).

1.2 Grouping and Administration

Quarantine-qualified animals with similar weights were selected for theexperiment. The mice were randomly grouped according to their weights,with five mice in each group, as shown in Table 1:

TABLE 1 Group Administration Dosage (mg/kg) Solvent 1 Blank controlintraperitoneal 0 sterile group injection water 2 Ulcerative colitisintraperitoneal 0 sterile model group injection water (dextran sodiumsulphate) 3 Positive control intramuscular 50 olive group injection oil(cyclosporine A) 4 Low-dose intraperitoneal 10 sterile treatment groupinjection water (Compound I-1) 5 Middle-dose intraperitoneal 20 steriletreatment group injection water (Compound I-1) 6 High-doseintraperitoneal 40 sterile treatment group injection water (CompoundI-1)

1.3 Experimental Method

Mice in the blank control group were given normal drinking waterthroughout the experiment. The other 5 groups of mice were givendrinking water containing 2% dextran sodium sulphate (DSS) from day 1 today 5, normal drinking water from day 6 to day 7, drinking watercontaining 2% dextran sodium sulphate from day 8 to day 12, and normaldrinking water from day 13 to day 14. The experiment ended on day 14.

Animals in the blank control group and ulcerative colitis model groupwere given sterile water intraperitoneally from day 1, once a day; theother 4 groups were administered according to table 1, once a day, untilthe end of the experiment on day 14. Two hours after the first day ofadministration, the mice were started to drink water containing dextransodium sulphate.

1.4 Measurement and Tissue Collection

(1) The mice were weighed daily.

(2) Blood samples were collected from the orbital vein on day 14 andstored at −80° C.

(3) On day 14, the mice were sacrificed by cervical vertebradislocation, the colon was removed and a small amount of fecal was takenfrom the colon and left as a sample. The colon length and colon weightwere measured. A portion of the colon and the fecal sample was stored at−80° C.

2. Experimental Results

As shown in Tables 2 and 3, the weight of the mice in the ulcerativecolitis model group was significantly reduced to 74.18% of the initialbody weight compared to the blank control group, and compound I-1 had asignificant ameliorating effect on the reduction in the weight of miceand showed a dose-dependent enhancement.

TABLE 2 Average weight of mice in each group Blank Ulcerative PositiveLow-dose Middle-dose High-dose control colitis model control treatmenttreatment treatment Group group group group group group group Day 1/g27.9 27.8 27.8 27.9 27.8 27.6 Day 2/g 27.9 27.7 27.7 28.1 27.8 27.6 Day3/g 28.0 27.6 27.7 28.0 27.9 27.6 Day 4/g 28.0 27.6 27.7 28.0 27.9 27.6Day 5/g 28.1 26.7 27.4 27.2 27.5 27.3 Day 6/g 28.1 25.8 27.4 26.3 27.227.2 Day 7/g 28.1 24.8 27.3 25.9 26.7 26.8 Day 8/g 28.1 23.9 27.3 25.626.2 26.3 Day 9/g 28.1 22.8 27.2 25.3 25.9 25.8 Day 10/g 28.4 22.1 27.124.9 25.6 25.6 Day 11/g 28.5 21.7 26.9 24.4 25.3 25.5 Day 12/g 28.6 21.426.7 24.1 25.0 25.4 Day 13/g 28.7 21.0 26.6 23.8 24.8 25.3 Day 14/g 28.720.7 26.6 23.7 24.7 25.2

TABLE 3 Rate of change in weight of mice in each group Blank UlcerativePositive Low-dose Middle-dose High-dose control colitis model controltreatment treatment treatment Group group group group group group groupDay 1/% 100.0 100.0 100.0 100.0 100.0 100.0 Day 2/% 100.2 99.5 99.6100.6 100.1 99.9 Day 3/% 100.4 99.1 99.4 100.5 100.3 100.0 Day 4/% 100.499.1 99.4 100.3 100.3 100.0 Day 5/% 100.6 96.1 98.5 97.6 99.1 99.1 Day6/% 100.6 92.9 98.3 94.3 97.8 98.7 Day 7/% 100.9 89.1 98.3 93.0 96.097.0 Day 8/% 100.9 85.8 98.1 91.6 94.3 95.3 Day 9/% 100.9 82.0 97.9 90.893.2 93.5 Day 10/% 102.0 79.6 97.3 89.1 92.2 92.7 Day 11/% 102.4 78.196.8 87.5 91.1 92.2 Day 12/% 102.7 76.8 96.0 86.4 90.0 92.0 Day 13/%102.9 75.6 95.6 85.3 89.2 91.5 Day 14/% 102.9 74.3 95.5 84.9 88.8 91.4

As shown in Table 4, compared with the blank control group, the colonlength of mice in the ulcerative colitis model group was significantlyshortened, and the average length was shortened from 7.18 cm to 5.02 cm.The administration of compound I-1 could gradually restore the length ofthe colon to normal and showed a dose-dependent effect, the high-dosetreatment group was even better than the positive control group.

TABLE 4 Average colon length of mice in each group Blank UlcerativePositive Low-dose Middle-dose High-dose control colitis model controltreatment treatment treatment Group group group group group group groupColon 7.18 5.02 6.36 5.46 6.04 6.52 length/cm

As shown in Table 5, compared with the blank control group, the colonweight of mice in the ulcerative colitis model group was significantlyincreased.

TABLE 5 Average colon weight of mice in each group Blank UlcerativePositive Low-dose Middle-dose High-dose control colitis model controltreatment treatment treatment Group group group group group group groupColon 0.1786 0.2017 0.1840 0.1909 0.2115 0.2129 weight/g

As shown in Table 6, compared with the blank control group, the unitcolon weight (colon weight/colon length) of mice in the ulcerativecolitis model group was significantly increased. The administration ofcompound I-1 could significantly improve the unit colon weight, and thehigh-dose group showed the best performance.

TABLE 6 Unit colon weight of mice in each group Blank UlcerativePositive Low-dose Middle-dose High-dose control colitis model controltreatment treatment treatment Group group group group group group groupUnit colon 0.0249 0.0395 0.0289 0.0351 0.0351 0.0327 weight (g/cm)

As shown in Tables 2 to 6 and FIG. 2 , after intraperitonealadministration of different concentrations, the reduction of weight andshortening of colon length of mice in the treatment groups weresignificantly relieved. Compared with the ulcerative colitis modelgroup, the unit colon weight in the treatment groups showed a decreasingtrend.

Effect example 2: Therapeutic effect of compound I-2, I-4, I-5, and I-6on ulcerative Colitis

1. Experimental Procedure

1.1 Experimental Animals and Experimental Conditions

Thirty-five 10-week-old male C57 mice, SPF class animal house,temperature 20-26° C., humidity 40%-70%, alternating light-dark periods(12 h/12 h).

1.2 Grouping and Administration

Quarantine-qualified animals with similar weights were selected for theexperiment. The mice were randomly grouped according to their weights,with five mice in each group, as shown in Table 7:

TABLE 7 Group Administration Dosage (mg/kg) Solvent 1 Blank control oralgavage 0 sterile group water 2 Ulcerative colitis oral gavage 0 sterilemodel group water (dextran sodium sulphate) 3 Positive control oralgavage 30 olive group (SASP) oil 4 Treatment group I-2 oral gavage 40sterile (compound I-2) water 5 Treatment group I-4 oral gavage 40sterile (compound I-4) water 6 Treatment group I-5 oral gavage 40sterile (compound I-5) water 7 Treatment group I-6 oral gavage 40sterile (compound I-6) water

Mice in the blank control group were given normal drinking waterthroughout the experiment. The other 6 groups of mice were givendrinking water containing 2% dextran sodium sulphate from day 1 to day5, normal drinking water from day 6 to day 7, drinking water containing2% dextran sodium sulphate from day 8 to day 12, and normal drinkingwater from day 13 to day 14. The experiment ended on day 14. All groupswere administered by oral gavage once a day according to table 7, untilthe end of the experiment on day 14.

1.3 Measurement and Tissue Collection

(1) The mice were weighed daily.

(2) Blood samples were collected from the orbital vein on day 14 andstored at −80° C.

(3) On day 14, the mice were sacrificed by cervical vertebradislocation, the colon was removed and a small amount of fecal was takenfrom the colon and left as a sample. The colon length and colon weightwere measured. A portion of the colon and the fecal sample was stored at−80° C.

2. Experimental Results

The experimental results are shown in Tables 8 to 9:

TABLE 8 Average weight of mice in each group Blank Ulcerative PositiveTreatment Treatment Treatment Treatment control colitis model controlgroup group group group Group group group group I-2 I-4 I-5 I-6 Day 1/g27.36 26.82 26.8 26.86 26.72 26.9 26.9 Day 2/g 27.44 26.88 26.86 26.926.76 26.92 26.94 Day 3/g 27.46 26.74 26.82 26.82 26.72 26.88 26.9 Day4/g 27.36 26.76 26.8 26.86 26.72 26.9 26.9 Day 5/g 27.4 26.04 26.5226.58 26.44 26.58 26.64 Day 6/g 27.36 25.44 25.74 26.48 26.36 26.32 26.2Day 7/g 27.42 24.34 24.38 25.18 24.82 25.3 24.52 Day 8/g 27.52 23.4422.92 23.78 23.44 23.6 24.38 Day 9/g 27.18 22.88 22.3 23.64 23.3 23.2424.42 Day 10/g 27.4 22.28 22.34 23.64 23.3 23.24 24.42 Day 11/g 27.522.08 22.68 24.72 24.02 24.2 24.66 Day 12/g 27.66 22.2 23.14 24.82 24.1424.48 24.94 Day 13/g 27.76 22.26 23.52 24.8 24.5 24.5 24.72 Day 14/g27.76 22.18 23.52 24.92 24.68 24.68 24.5

TABLE 9 Average colon length of mice in each group Blank UlcerativePositive Treatment Treatment Treatment Treatment control colitis modelcontrol group group group group Group group group group I-2 I-4 I-5 I-6Colon 7.1 5.8 6.0 6.2 6.2 6.0 5.9 length/cm

The results showed that the weight of mice in the ulcerative colitismodel group was significantly lower compared to the blank control group,and oral gavage administration of compounds I-2, I-4, I-5, and I-6 had asignificant improvement in the reduction of weight in mice, and all ofcompounds I-2, I-4, I-5, and I-6 were better than the positive controldrug salazosulfapyridine (SASP).

Effect Example 3: Therapeutic Effect of Compound I-1, I-2, and I-7 toI-12 on Ulcerative Colitis

1. Experimental Procedure

1.1 Experimental Animals and Experimental Conditions

Fifty 10-week-old male C57 mice, SPF class animal house, temperature20-26° C., humidity 40%-70%, alternating light-dark periods (12 h/12 h).

1.2 Grouping and Administration

Quarantine-qualified animals with similar weights were selected for theexperiment. The mice were randomly grouped according to their weights,with five mice in each group, as shown in Table 10:

TABLE 10 Group Administration Dosage (mg/kg) Solvent 1 Blank controloral gavage 0 sterile group water 2 Ulcerative colitis oral gavage 0sterile model group water (dextran sodium sulphate) 3 Treatment groupI-1 oral gavage 40 sterile (compound I-1) water 4 Treatment group I-2oral gavage 40 sterile (compound I-2) water 5 Treatment group I-7 oralgavage 40 sterile (compound I-7) water 6 Treatment group I-8 oral gavage40 sterile (compound I-8) water 7 Treatment group I-9 oral gavage 40sterile (compound I-9) water 8 Treatment group I-10 oral gavage 40sterile (compound I-10) water 9 Treatment group I-11 oral gavage 40sterile (compound I-11) water 10 Treatment group I-12 oral gavage 40sterile (compound I-12) water

Mice in the blank control group were given normal drinking waterthroughout the experiment. The other 9 groups of mice were givendrinking water containing 2% dextran sodium sulphate from day 1 to day7. All groups were administered by oral gavage once a day according totable 10, until the end of the experiment.

1.3 Measurement and Tissue Collection

(1) The mice were weighed daily.

(2) Blood samples were collected from the orbital vein on day 7 andstored at −80° C.

(3) On day 7, the mice were sacrificed by cervical vertebra dislocation,the colon was removed and a small amount of fecal was taken from thecolon and left as a sample. The colon length and colon weight weremeasured. A portion of the colon and the fecal sample was stored at −80°C.

2. Experimental Results

The experimental results are shown in Tables 11 to 12:

TABLE 11 Average weight of mice in each group Weight of mice Day 1/g Day2/g Day 3/g Day 4/g Day 5/g Day 6/g Day 7/g Blank control group 21.0521.38 21.40 21.15 20.80 21.38 21.43 Ulcerative colitis 21.82 21.97 21.9221.68 20.40 19.52 18.47 model group Treatment group I-1 21.33 20.9720.80 20.85 20.53 20.13 19.82 Treatment group I-2 21.53 21.42 21.2520.97 20.72 20.27 19.27 Treatment group I-7 21.47 21.62 21.18 20.8220.13 20.07 19.88 Treatment group I-8 21.85 21.97 21.77 21.33 20.6220.52 20.32 Treatment group I-9 21.20 21.17 20.92 20.47 20.03 19.4219.38 Treatment group I-10 21.95 21.60 21.18 21.27 20.90 20.13 19.25Treatment group I-11 21.62 21.30 21.10 20.97 20.32 19.93 19.30 Treatmentgroup I-12 21.25 21.22 21.13 20.62 20.10 16.32 18.88

TABLE 12 Average colon length of mice in each group Blank ulcerativeTreatment Treatment Treatment Treatment Treatment Treatment TreatmentTreatment control colitis model group group group group group groupgroup group Group group group I-1 I-2 I-7 I-8 I-9 I-10 I-11 I-12 Colon7.2 5.1 6.2 5.8 5.4 6.1 6.3 5.8 6.2 5.7 length/cm

The results showed that the weight of mice in the ulcerative colitismodel group was significantly lower compared to the blank control group;except for compound I-11, all the tested compounds by oral gavageadministration had a significant improvement in the reduction of weightin mice. In addition, oral gavage administration of I-1, I-8, I-9, andI-11 can gradually restore the colon length.

Although the examples of the invention have been described herein, thoseskilled in the art should understand that the examples are merelyillustrative, and various changes may be made to the examples withoutdeparting from the principle and spirit of the invention. Therefore, thescope of the invention is to be limited by the appended claims.

What is claimed is:
 1. A compound represented by formula A-1, apharmaceutically acceptable salt thereof, a solvate thereof, or acrystal form thereof,

wherein R¹, R², R³, and R⁴ are independently hydrogen, C₁₋₄ alkyl,benzyl, —C(═O)R, or —C(═O)—O—R′, and R¹, R², R³, and R⁴ are notsimultaneously hydrogen; each R¹ is independently C₁₋₄ alkyl; each R isindependently C₁₋₄ alkyl or phenyl; R⁵ and R⁶ are independentlyhydrogen, or R⁵ and R⁶ are taken together to form ═O; R⁸ and R⁹ areindependently C₁₋₄ alkyl; alternatively, R⁸ and R⁹ are taken togetherwith the carbon atom to which they are attached to form 3- to 7-memberedcycloalkyl, 3- to 7-membered heterocycloalkyl, 3- to 7-memberedcycloalkyl substituted with one or a plurality of R^(a), or 3- to7-membered heterocycloalkyl substituted with one or a plurality ofR^(b); in the 3- to 7-membered heterocycloalkyl and the 3- to 7-memberedheterocycloalkyl substituted with one or a plurality of R^(b), theheteroatoms in the 3- to 7-membered heterocycloalkyl are independentlyselected from N, O, and S, and the number of heteroatoms isindependently 1, 2, or 3; R^(a) and R^(b) are independently C₁₋₄ alkyl,—C(═O)R″; each R″ is independently C₁₋₄ alkyl; carbon atoms marked with“*” indicate that when the carbon atoms are chiral, the carbon atoms arein the R-configuration, S-configuration, or a mixture of R-configurationand S-configuration.
 2. The compound represented by formula A-1, thepharmaceutically acceptable salt thereof, the solvate thereof, or thecrystal form thereof as claimed in claim 1, wherein the structure of thecompound represented by formula A-1 is as follows:

wherein R¹, R², R³, and R⁴ are independently hydrogen, C₁₋₄ alkyl,benzyl or —C(═O)R, and R¹, R², R³, and R⁴ are not simultaneouslyhydrogen; each R is independently C₁₋₄ alkyl or phenyl.
 3. The compoundrepresented by formula A-1, the pharmaceutically acceptable saltthereof, the solvent thereof, or the crystal form thereof as claimed inclaim 1, wherein when R¹, R², R³, and R⁴ are independently C₁₋₄ alkyl,then the C₁₋₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, or tert-butyl; or, each R¹ is independently methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;or, when each R is independently C₁₋₄ alkyl, then the C₁₋₄ alkyl ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ortert-butyl; or, when R⁸ and R⁹ are independently C₁₋₄ alkyl, then theC₁₋₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, or tert-butyl; or, when R⁸ and R⁹ are taken together with thecarbon atom to which they are attached to form 3- to 7-memberedcycloalkyl or 3- to 7-membered cycloalkyl substituted with one or aplurality of R^(a), then the 3- to 7-membered cycloalkyl is a 5- to6-membered cycloalkyl; or, when R⁸ and R⁹ are taken together with thecarbon atom to which they are attached to form 3- to 7-memberedheterocycloalkyl or 3- to 7-membered heterocycloalkyl substituted withone or a plurality of R^(b), in the 3- to 7-membered heterocycloalkyl,the heteroatoms are independently selected from N and O, and the numberof heteroatoms is independently 1; or, when R⁸ and R⁹ are taken togetherwith the carbon atom to which they are attached to form 3- to 7-memberedheterocycloalkyl or 3- to 7-membered heterocycloalkyl substituted withone or a plurality of R^(b), then the 3- to 7-membered heterocycloalkylis a 5- to 6-membered heterocycloalkyl; or, when R^(a) and R^(b) areindependently C₁₋₄ alkyl, then the C₁₋₄ alkyl is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or,each R″ is independently methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, or tert-butyl.
 4. The compound represented byformula A-1, the pharmaceutically acceptable salt thereof, the solventthereof, or the crystal form thereof as claimed in claim 3, wherein whenR¹, R², R³, and R⁴ are independently C₁₋₄ alkyl, then the C₁₋₄ alkyl ismethyl; or, each R¹ is independently ethyl; or, when each R isindependently C₁₋₄ alkyl, then the C₁₋₄ alkyl is methyl or tert-butyl;or, when R⁸ and R⁹ are independently C₁₋₄ alkyl, then the C₁₋₄ alkyl ismethyl; or, when R⁸ and R⁹ are taken together with the carbon atom towhich they are attached to form 3- to 7-membered heterocycloalkyl, then

is

or, each R″ is independently methyl; or, when R⁸ and R⁹ are takentogether with the carbon atom to which they are attached to form 3- to7-membered heterocycloalkyl substituted with one or a plurality ofR^(b), then

is


5. The compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvent thereof, or the crystal formthereof as claimed in claim 1, wherein R¹, R², R³, and R⁴ areindependently hydrogen, C₁₋₄ alkyl, —C(═O)R, or —C(═O)—O—R′; or, each Ris independently C₁₋₄ alkyl; or, R^(a) and R^(b) are independently—C(═O)R″; or, R⁸ and R⁹ are independently C₁₋₄ alkyl, or, R⁸ and R⁹ aretaken together with the carbon atom to which they are attached to form3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or 3- to7-membered heterocycloalkyl substituted with one or a plurality ofR^(b); or

is


6. The compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof as claimed in claim 5, wherein R¹ is C₁₋₄ alkyl, —C(═O)R, or—C(═O)—O—R′; or, when R⁵ and R⁶ are independently hydrogen, then R¹ is—C(═O)R or —C(═O)—O—R′; when R⁵ and R⁶ are taken together to form =0,then R¹ is C₁₋₄ alkyl; or, R² and R³ and R⁴ are independently hydrogenor —C(═O)R; or, each R is independently methyl or tert-butyl; or, R^(a)and R^(b) are independently

or, R⁸ and R⁹ are independently C₁₋₄ alkyl, or, R⁸ and R⁹ are takentogether with the carbon atom to which they are attached to form 3- to7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

is


7. The compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof as claimed in claim 5, wherein R¹ is methyl,

or, R², R³, and R⁴ are independently hydrogen,

or, R², R³, and R⁴ are the same group; or,

is


8. The compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof as claimed in claim 2, wherein R¹, R², R³, and R⁴ areindependently hydrogen or —C(═O)R; or, each R is independently C₁₋₄alkyl.
 9. The compound represented by formula A-1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, or the crystal formthereof as claimed in claim 2, wherein when R¹, R², R³ and R⁴ areindependently C₁₋₄ alkyl, then the C₁₋₄ alkyl is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or,each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, or phenyl; or, R¹, R², R³, and R⁴ arethe same group; or, the structure of the said compound represented byformula A is as follows:

or a mixture of

in a molar ratio of 1:1
 10. The compound represented by formula A-1, thepharmaceutically acceptable salt thereof, the solvent thereof, or thecrystal form thereof as claimed in claim 1, wherein the compoundrepresented by formula A-1 is any of the following compounds,


11. A pharmaceutical composition comprising a compound as represented byformula A-1, a pharmaceutically acceptable salt thereof, and apharmaceutical adjuvant;

wherein R¹, R², R³, and R⁴ are independently hydrogen, C₁₋₄ alkyl,benzyl, —C(═O)R, or —C(═O)—O—R; R, R′, *, R⁵, R⁶, R⁸, and R⁹ are definedas claimed in claim
 1. 12. The pharmaceutical composition as claimed inclaim 11, wherein the structure of the compound represented by formulaA-1 is as follows:

wherein R¹, R², R³, and R⁴ are independently hydrogen, C₁₋₄ alkyl,benzyl, —C(═O)R; R is defined as above.
 13. The pharmaceuticalcomposition as claimed in claim 11, wherein the pharmaceuticalcomposition is a pharmaceutical composition for treating inflammatorybowel disease; or, when R¹, R², R³, and R⁴ are independently C₁₋₄ alkyl,then the C₁₋₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, or tert-butyl; or, R¹, R², R³, and R⁴ areindependently hydrogen, —C(═O)R, or —C(═O)—O—R′; or, R², R³, and R⁴ arethe same group; or,

is

or, the structure of the compound represented by formula A is asfollows:

or a mixture of

in a molar ratio of 1:1.
 14. The pharmaceutical composition as claimedin claim 11, wherein R¹ is C₁₋₄ alkyl, C(═O)R, or —C(═O)—O—R′; or, R²,R³, and R⁴ are independently hydrogen or —C(═O)R; or, when R⁵ and R⁶ areindependently hydrogen, then R¹ is —C(═O)R or —C(═O)—O—R′; when R⁵ andR⁶ are taken together to form ═O, then R¹ is C₁₋₄ alkyl; or,

is

or, the structure of the compound represented by formula A is asfollows:


15. The pharmaceutical composition as claimed in claim 11, wherein R¹ ismethyl,

or, R², R³, and R⁴ are independently hydrogen,


16. The pharmaceutical composition as claimed in claim 11, wherein thestructure of the compound represented by formula A-1 is any of thefollowing compounds:

17-18. (canceled)
 19. A crystal form of a compound represented byformula I-2,

the unit cell parameters of the compound represented by formula I-2 are:a=10.5391(3) Å, α=90°; b=14.2167(4) Å, β=90°; c=15.9116(5) Å, γ=90°;space group P2₁2₁2₁; preferably: Empirical formula C₂₂H₂₈O₁₂ Formulaweight 484.44 Temperature 169.99 K Wavelength 1.34139 Å Crystal systemOrthorhombic system Space group P2₁2₁2₁ Unit cell dimensions a =10.5391(3) Å, α = 90° b = 14.2167(4) Å, β = 90° c = 15.9116(5) Å, γ =90° Unit cell volume 2384.05(12) Å³ Z 4 Density (calculated) 1.350 Mg/m³Absorption coefficient 0.607 mm⁻¹ F(000) 1024 Crystal size 0.12 × 0.1 ×0.05 mm³ Theta range for 5.148 to 54.935° data collection Index ranges−12 <= h <= 12, −15 <= k <= 17, −19 <= l <= 19 Reflections collected21844 Independent reflections 4478 [R(int) = 0.0451] Refinement methodFull-matrix least-squares on F²


20. A pharmaceutical composition comprising the crystal form of thecompound represented by formula I-2 as claimed in claim 19 and apharmaceutical adjuvant; the pharmaceutical composition is preferably apharmaceutical composition for treating inflammatory bowel disease; thesaid inflammatory bowel disease is preferably ulcerative colitis. 21-23.(canceled)
 24. A method of treating inflammatory bowel disease,comprising administrating a therapeutically effective amount ofsubstance A to a patient; the substance A comprises a compoundrepresented by formula A-1, a pharmaceutically acceptable salt thereof,a solvate thereof, a crystal form thereof, or a pharmaceuticalcomposition thereof;

wherein R¹, R², R³, and R⁴ are independently hydrogen, C₁₋₄ alkyl,benzyl, —C(═O)R, or —C(═O)—O—R′; *, R⁵, R⁶, R⁸, and R⁹ are defined inclaim 1.